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Cell-Surface Glycan-Lectin Interactions for Biomedical Applications CELL-SURFACE GLYCAN-LECTIN INTERACTIONS FOR BIOMEDICAL APPLICATIONS by Maria Carolina Rodriguez Benavente A Dissertation Submitted to the Faculty of The Charles E. Schmidt College of Science in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Florida Atlantic University Boca Raton, FL May 2015 Copyright 2015 by Maria Carolina Rodriguez Benavente ii ACKNOWLEDGEMENTS “Self-made people don’t exist. Anyone who has enjoyed success in the life is able to do so because they have been helped by others. And I can tell you that when it comes to the massive turnaround that my life has taken, it has not been a solo journey.” - From “Growing Into Grace” by Mastin Kipp. I am not a one-woman show. Any success I have had in life, is a result of numerous people who have supported me along the way. To my mentor, Dr. Predrag Cudic, thank you for allowing me the opportunity to grow as a research professional in your lab. I would like to thank my Graduate Committee Members, Dr. Salvatore Lepore, Dr. Adel Nefzi, and Dr. Lyndon West, for all of your support, guidance, advice, and encouragement throughout my graduate degree. To my other mentor, Dr. Mare Cudic, thank you for believing in me. One of the most gratifying experiences I have had along my graduate years was working at The Torrey Pines Institute for Molecular Studies. Dr. Richard Houghten, thank you for making me a part of the TPIMS family. To all the faculty and staff at the Institute, your support has never gotten unnoticed, and I for one will never forget it. To the friends and colleagues I met at the Institute, specially Dr. Ania Knapinska, Dr. Sabrina Amar, Ginamarie Debevec, and Laura Maida. It has been an honor and a pleasure working and growing alongside with you. They say you are as special as the people you surround yourself with. Well, in that case, I am blessed. Most importantly, to my family. If there was ever any unconditional support I received, was from you. Thank you for believing in me even when I was uncertain. Thank you for being my cornerstone of love and reassurance, especially at times when it felt strenuous and exhausting to continue. I made it through because of you, mom and dad. Thank you. iv ABSTRACT Author: Maria Carolina Rodriguez Benavente Title: Cell-Surface Glycan-Lectin Interactions for Biomedical Applications Institution: Florida Atlantic University Dissertation Co-advisors: Dr. Salvatore D. Lepore Dr. Predrag Cudic Degree: Doctor of Philosophy Year: 2015 Carbohydrate recognition is one of the most sophisticated recognition processes in biological systems, mediating many important aspects of cell-cell recognition, such as inflammation, cell differentiation, and metastasis. Consequently, lectin-glycan interactions have been intensively studied in order to mimic their actions for potential bioanalytical and biomedical applications. Galectins, a class of ß-galactoside-specific animal lectins, have been strongly implicated in inflammation and cancer. Galectin-3 is involved in carbohydrate-mediated metastatic cell heterotypic and homotypic adhesion via interaction with Thomsen-Friedenreich (TF) antigen on cancer-associated MUC1. However, the precise mechanism by which galectin-3 recognizes TF antigen is poorly understood. Our thermodynamic studies have shown that the presentation of the carbohydrate ligand by MUC1-based peptide scaffolds can have a major impact on recognition, and may facilitate the design of more potent and specific galectin-3 inhibitors that can be used as novel chemical tools in dissecting the precise role of galectin-3 in cancer and inflammatory diseases. Another lectin, odorranalectin (OL), has been recently identified from Odorrana grahami skin secretions as the smallest cyclic peptide lectin, has a particular selectivity for L-fucose and very low toxicity and immunogenicity, rendering OL an excellent candidate for drug delivery to targeted sites, such as: (1) tumor-associated fucosylated antigens implicated in the pathogenesis of several cancers, for overcoming the nonspecificity of most anticancer agents; (2) the olfactory v epithelium of nasal mucosa for enhanced delivery of peptide-based drugs to the brain. Described in this dissertation is a simple and robust approach toward the solid-phase synthesis of OL and its analogs, based on standard Fmoc-solid phase peptide synthesis protocols. Lectin-cell staining studies reveal preferential binding towards cancer cell lines that overexpress fucosylated antigens on their cell surface when compared to healthy cells. In addition, our in vivo mice studies show fast intranasal delivery of OL to mouse brain in amounts detectable by mass spectrometry, thus offering a novel brain drug delivery system for the treatment of central nervous system (CNS) disorders. Altogether, the research described in this dissertation demonstrates that new ‘lectin- mimicking’ peptides related to lectins or their target glycans have the potential to be used: as sensors for detection, diagnosis, and prognosis, as “blockers/inhibitors” for therapeutics development, and as vectors for the targeted delivery of imaging and therapeutic agents. vi DEDICATION This work is fully dedicated to my aunt Carolina and my grandmother Juanita. Thank you for being my endless flame of inspiration and determination. “I am no master, I know nothing I am no master, I know nothing But I am a servant and I know something I am no master, I know nothing.” - Excerpt lyrics from “Black as Night” by Nahko and Medicine for the People CELL-SURFACE GLYCAN-LECTIN INTERACTIONS FOR BIOMEDICAL APPLICATIONS LIST OF TABLES ............................................................................................................................ xii LIST OF FIGURES ......................................................................................................................... xiii LIST OF SCHEMES ....................................................................................................................... xvi LIST OF ABBREVIATIONS .......................................................................................................... xvii CHAPTER 1 INTRODUCTION ........................................................................................................ 1 1.1. Overview - carbohydrate recognition in biological systems ............................................. 1 1.2. Principles of glycan recognition........................................................................................ 5 1.2.1. The “cluster glycoside effect” in carbohydrate recognition ...................................... 7 1.2.2. Cooperativity vs. polyvalency ................................................................................. 11 1.2.3. Enthalpy of a polyvalent interaction ....................................................................... 13 1.2.4. Entropy of a polyvalent interaction ......................................................................... 13 1.3. Lectins ............................................................................................................................ 16 1.3.1. Types of lectins ...................................................................................................... 19 1.4. Lectin-carbohydrate interactions: towards therapeutic and diagnostic applications ................................................................................................................................ 25 1.6. Research goals .............................................................................................................. 27 CHAPTER 2 THERMODYNAMIC ASSESSMENT OF MUC1-TYPE GLYCOPEPTIDES AND ITS EFFECT ON GALECTIN-3 BINDING ............................................................................. 30 2.1. Overview ........................................................................................................................ 30 2.2. Galectin-3 ....................................................................................................................... 30 2.3. The Thomsen-Friedenreich antigen (TF) and its role in cancer ..................................... 31 viii 2.4. MUC1 glycopeptides ...................................................................................................... 36 2.5. Peptide modification by glycosylation ............................................................................ 37 2.6. Thermodynamic assessment study ............................................................................... 38 2.6.1. Assessment of binding interaction of glycosides with galectin-3 ........................... 38 2.6.2. Assessment of binding interaction of glycopeptides with galectin-3 ...................... 40 2.7. Discussion and conclusions ........................................................................................... 44 2.8. Materials and methods ................................................................................................... 46 2.8.1. Chemicals and instrumentation .............................................................................. 46 2.8.2. Bacterial strains and reagents ................................................................................ 46 2.8.3. Galectin-3/Gal3C expression and purification ........................................................ 46 2.8.4. Isothermal titration calorimetry measurements ...................................................... 48 CHAPTER 3 STRUCTURAL MODIFICATION OF NATIVE ODORRANALECTIN (OL) PEPTIDES AND ITS EFFECT ON STABILITY,
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